Project ID CM-HD2024_23


Co Supervisor 1A Faculty of Life Sciences & Medicine, School of Cancer & Pharmaceutical Sciences, Institute of Pharmaceutical ScienceWebsite

Co Supervisor 1B Faculty of Life Sciences & Medicine, School of Cancer & Pharmaceutical Sciences, Institute of Pharmaceutical ScienceWebsite

Characterising the role of AKT kinase function in SREBP2-regulated cholesterol homeostasis in human cancer

AKT is a serine/threonine kinase that regulates several important cellular processes including growth, metabolism, and survival. It is aberrantly activated in a majority of human cancers, and has consequently been pursued as a therapeutic target, with multiple AKT inhibitors currently undergoing clinical testing. However, the therapeutic benefit of these drugs has not been as broad as predicted by the frequency of AKT activation. Although AKT activity has been linked to the regulation of cholesterol metabolism, the molecular details of this regulation remain incompletely understood. This PhD project will investigate the role of AKT in modulating the function of SREBP2, a master regulator of intracellular cholesterol. Given the importance of cholesterol in supporting oncogenic growth, data from this project will be critical in understanding how AKT inhibitors suppress tumour growth, and could help to refine current AKT-targeting approaches to improve therapeutic response. Preliminary data from the Vivanco lab show that 1) AKT phosphorylates SCAP, a chaperone protein required for SREBP2 activation, and 2) AKT perturbations affect intracellular cholesterol levels. This project has three main aims: in year one the student will identify the relevant AKT phosphorylation sites on SCAP; in year two, they will assess the impact of mutation of these sites on SCAP chaperoning function and SREBP2 activation, and in year three and at the beginning of year four they will assess the relevance of AKT-driven phosphorylation of SCAP on the response of cancer cells and their metabolism to AKT inhibitors, alone or in combination with cholesterol modulating drugs (e.g. statins). Through this project, the student will gain important skills in cell biology (e.g. various advanced microscopy techniques) cancer pharmacology (e.g. assessment of drug response, pharmacodynamic and pharmacokinetic measurements), and cellular metabolism (e.g. assessment of metabolic changes using NMR and/or mass spectrometry-based methods).

Representative Publications

1. “A systematic molecular and pharmacologic evaluation of AKT inhibitors reveals new insight into their biological activity”, Kostaras E, Kaserer T, Lazaro G, Heuss SF, Hussain A, Casado P, Hayes A, Yandim C, Palaskas N, Yu Y, Schwartz B, Raynaud F, Chung YL, Cutillas PR & Vivanco I., (2020), Br J Cancer. doi: 10.1038/s41416- 020-0889-4 2. “DUSP4 protects BRAF- and NRAS-mutant melanoma from oncogene overdose through modulation”, Gutierrez-Prat, N., Zuberer, H.L., Mangano, L., Karimaddini, Z., Wolf, L., Tyanova, S., Wellinger, L.C., Marbach, D., Griesser, V., Pettazzoni, P., Bischoff, J.R., Rohle, D., Palladino, C. & Vivanco, I., (2022), Life Sci Alliance. 5(9):e202101235. doi: 10.26508/lsa.202101235 3. “Inhibitors in AKTion: ATP-competitive vs allosteric.”, Lazaro G., Kostaras E. and Vivanco I., (2020), Biochem Soc Trans. doi: 10.1042/BST20190777
1. “Nuclear magnetic resonance metabolomics of symbioses between bacterial vaginosis associated bacteria”, Horrocks, V., Hind, C. K., Wand, M. E., Fady, P-E., Chan, J., Hopkins, J., Houston, G., Tribe, R., Sutton, J. & Mason, J., (2022), mSphere, 7(3), e0016622. 2. “Impacts of metabolism and organic acids on cell wall composition and Pseudomonas aeruginosa susceptibility to membrane active antimicrobials”, Manzo, G., Gianfanti, F., Hind, C. K., Allison, L., Clarke, M., Hohenbichler, J., Limantoro, I., Martin, B., Do Carmo Silva, P., Ferguson, P., Hodgson-Casson, A., Fleck, R., Sutton, J. M., Phoenix, D. & Mason, J., (2021), ACS Infectious Diseases 7.8 (2021): 2310-2323